The present invention relates to a new crystal modification of N-(1-methylethyl aminocarbonyl)-4-(3-methyl-phenylamino)-3-pyridinesulfonamide (in the further text of the application designated by its generic name xe2x80x9ctorasemidexe2x80x9d), particularly to a new crystal modification III of torasemide, to processes for its preparation, to its use as a raw material for the preparation of the crystal modification I of torasemide and of pharmaceutically acceptable salts of torasemide as well as to pharmaceutical forms containing the said new modification III of torasemide as the active ingredient.
Torasemide is a compound with interesting pharmacological properties, which is described in DE patent 25 16 025 (Example 71). As a diuretic of Henle""s loop it is useful as an agent for preventing heart or heart tissue damages caused by metabolic or ionic abnormalities associated with ischemia, in the treatment of thrombosis, angina pectoris, asthma, hypertension, nephroedema, pulmonary edema, primary and secondary aldosteronism, Bartter""s syndrome, tumours, glaucoma, decreasing of intraocular pressure, acute or chronic bronchitis, in the treatment of cerebral edema caused by trauma, ischemia, concussion of the brain, metastases or epileptic attacks and in the treatment of nasal infections caused by allergens.
The ability of a substance to exist in more than one crystal form is defined as polymorphism and these different crystal forms are named xe2x80x9cpolymorph modificationsxe2x80x9d or xe2x80x9cpolymorphsxe2x80x9d. In general, polymorphism is affected by the ability of a molecule of a substance to change its conformation or to form different intermolecular or intra-molecular interactions, particularly hydrogen bonds, which is reflected in different atom arrangements in the crystal lattices of different polymorphs. Polymorphism is found in several organic compounds. Among medicaments polymorphism is found in about 70% of barbiturates, 60% of sulfonamides and 60% of steroids and about 50% of medicaments of the said classes are not present on the market in their most stable forms (T. Laird, Chemical Development and Scale-up in the Fine Chemical Industry, Principles and Practices, Course Manual, Scientific Update, Wyvern Cottage, 1996).
The different polymorphs of a substance possess different energies of the crystal lattice and, thus, in solid state they show different physical properties such as form, density, melting point, colour, stability, dissolution rate, milling facility, granulation, compacting, etc., which in medicaments may affect the possibility of the preparation of pharmaceutical forms, their stability, dissolution and bioavailability and, consequently, their action.
Polymorphism of medicaments is the object of studies of interdisciplinar expert teams [J. Haleblian, W. McCrone, J. Pharm. Sci. 58 (1969) 911; L. Borka, Pharm. Acta Helv. 66 (1991) 16; M. Kuhnert-Brandstxc3xa4tter, Pharmazie 51 (1996) 443; H. G. Brittain, J. Pharm. Sci. 86 (1997) 405; W. H. Streng, DDT 2 (1997) 415; K. Yoshii, Chem. Pharm. Bull. 45 (1997) 338, etc.] since a good knowledge of polymorphism represents a precondition for a critical observation of the whole process of medicament development. Thus, at deciding on the production of a pharmaceutical form in solid state and with regard to the dose size, stability, dissolution and anticipated action, it is necessary to determine the existence of all solid state forms (on the market some computer programmes can be found, e.g.  greater than  greater than Polymorph less than  less than  as a module of  greater than  greater than Cerius2 less than  less than  programme, MSI Inc., USA) and to determine the stability, dissolution and thermodynamic properties of each of them. Only on the basis of these determinations the appropriate polymorph can be selected for the development of pharmaceutical formulations.
From the great number of such efforts only a few will be mentioned. Thus, Gordon et al. (U.S. Pat. No. 4,476,248) protected a new crystal form of ibuprofen and a process for the preparation thereof; Bunnell et al. (EP 733 635) protected a new crystal form, a process for preparation thereof and a pharmaceutical formation of the medicament olanzapine containing this new crystal form; R. B. Gandhi et al. (EP 749 969) protected a new process for the preparation of polymorph form I of stavudine from a mixture of one or more forms I, II and III; A. Caron et al. (EP 708 103) protected a new crystal form of irbesartane, a process for the preparation thereof and pharmaceutical formulations containing this crystal form.
It is known [Acta Cryst. B34 (1978), 2659-2662 and Acta Cryst. B34 (1978), 1304-1310] that torasemide can exist in two crystal modifications differing with regard to the parameters of a single cell, which is confirmed by X-ray diffraction on their monocrystals. Both modifications are formed simultaneously by the slow evaporation of the solvent from a solution of torasemide in a mixture petroleum ether/ethanol. The modification I with melting point 169xc2x0 C. crystallizes monoclinically in the space group P 21/c (prisms), while the modifications II with melting point 162xc2x0 C. crystallizes monoclinically in the space group P 2/n (foils). Additionally, for the modification I the melting point 169.22xc2x0 C. is stated in Iyakuhin Kenkyu 25 (1994), 734-750.
According to Example 71 of DE 25 16 025 torasemide in a crystal form with melting point 163-164xc2x0 C. is obtained.
In U.S. Pat. No. 4,743,693 and U.S. reissue 34,580 or U.S. Pat. No. 4,822,807 and U.S. reissue 34,672 there is disclosed a process for the preparation of a stable modification I of torasemide from an unstable modification II of torasemide by adding a catalytic amount (1%) of a stable modification I of torasemide into a suspension of the unstable modification in water and stirring the mixture at a temperature from room temperature to 90xc2x0 C. within 3 hours to 14 days. In U.S. Pat. No. 4,743,693 and U.S. reissue 34,580 it is stated that the stable modification I of torasemide (monoclinic, space group P21/c) has a melting point of 162xc2x0 C. and the unstable modification II of torasemide (monoclinic, space group P 2/n) has a melting point 169xc2x0 C., which is contrary to the statements in Acta Cryst. B34 (1978), 2659-2662, Acta Cryst. B34 (1978), 1304-1310 and Iyakuhin Kenkyu 25 (1994), 734-750.
In the abstract of U.S. Pat. No. 4,822,807 the authors ascribe the melting point 162xc2x0 C. to the stable polymorph I of torasemide and the melting point 169xc2x0 C. to the unstable polymorph II of torasemide, whereas in the claims of the said patent different melting points for either polymorph are stated, namely for polymorph I the melting point 169xc2x0 C. and for polymorph II the melting point 162xc2x0 C.
In the abstract of U.S. reissue 34,672 the authors ascribe the melting point 162xc2x0 C. to the pure modifications I of torasemide and the melting point 169xc2x0 C. to the modification II of torasemide, whereas in the claims the melting point 159-161.5xc2x0 C. for the pure polymorph I and the melting point from about 157.5 to about 160xc2x0 C. for the unstable polymorph II are stated.
It has now been surprisingly found that by a controlled acidifying of alkaline solutions of torasemide with inorganic or organic acids with or without addition of a seed crystal at a temperature between 0 and 35xc2x0 C. within 15 minutes to 25 hours, a new crystal modification III of torasemide can be prepared.
By the alkaline solutions of torasemide according to the process of the present invention there are meant an alkaline extract of the original reaction mixture for the synthesis of torasemide, alkaline solutions of any crystal modification I, II or III of torasemide or alkaline solutions of any mutual mixtures of crystal modifications I, II or III of torasemide.
In the process of the present invention for the preparation of alkaline solutions of torasemide modifications, water solutions of lithium, sodium and potassium hydroxide as well as water solutions of sodium and potassium carbonate can be used.
The acidifying of the alkaline torasemide solutions according to the invention can be performed in inorganic acids such as hydrochloric, sulfuric, phosphoric and nitric acids and in organic acids such as formic, acetic, propionic, oxalic, tartaric, methanesulfonic and p-toluenesulfonic acids.
As the seed crystal in the processes of the present invention crystal powder of one of the isostructure substances, particularly crystal powder of the crystal modification III of torasemide can be used.
It has additionally been found that by using the process of the present invention no decomposition of torasemide occurs and the impurities that may be present in the alkaline extract of the original reaction mixture for the synthesis of torasemide or in modifications I, II or III of torasemide pass, by the present process, into bases, i.e. a chemically pure crystal modification III of torasemide is obtained.
Moreover, it has been found that the new crystal modification III of torasemide is stable under normal storage conditions as well as at being subjected to increased humidity, which means that it is neither transformed into the unstable modification II of torasemide nor into the stable modification I of torasemide.
The new crystal modification III of torasemide has a characteristic X-ray powder pattern obtained by X-ray diffraction on a powder sample of the new crystal modification III of torasemide in the instrument PHILIPS PW3710 under Cu X-rays [xcex(CuKxcex11)=1.54046 xc3x85 and xcex(CuKxcex12)=1.54439 xc3x85]. Thus obtained characteristics spacings between lattice planes designated by  greater than  greater than d less than  less than  and expressed in Angstrxc3x6m units and their corresponding characteristic relative intensities designated by  greater than  greater than I/I0 less than  less than  and expressed in % are represented in Table 1.
In addition, by recording the monocrystal of the new crystal modification III of torasemide in four circle PHILIPS PW 1100/StoeandCie diffractometer under Mo X-rays [xcex(MoKxcex1)=0.71073 xc3x85] there were obtained the basic crystallographic data for a single cell, which show in comparison with the literature data for crystal modifications I and II of torasemide [Acta Cryst. B34 (1978), 2659-2662 and Acta Cryst. B34 (1978), 1304-1310] that this is an absolutely new crystal modification III of torasemide.
The basic crystallographic data (diffraction on monocrystal) for modifications I, II and the new crystal modification III of torasemide are represented in Table 2.
The new crystal modification III of torasemide prepared according to the process of the present invention can be transformed by the use of common processes to the crystal modification I of torasemide, i.e. it can be used as a starting material for the preparation of known crystal modification I of torasemide.
The new crystal modification III of torasemide prepared according to the invention can be transformed to pharmaceutically acceptable salts of torasemide by the use of common processes.
The dissolution profile (USP 23) of the new crystal modification III of toresamide in water and in artificial intestinal juice in comparison to dissolution profiles of known crystal modifications I and II of toresamide, in the same fluids, shows a significant difference.
IDR (Intrinsic Dissolution Rate) of the new crystal modification III of torasemide in a model of artificial gastric juice exceeds 1 mg cmxe2x88x922minxe2x88x921, which indicates a potential good bioavailability.
The new crystal modification III of torasemide is prepared according to the process of the present invention in the form of a flowable crystal powder of a prismatic habitude, which exhibits flowability, i.e. it comes in a xe2x80x9cfree flowxe2x80x9d form, wherein no static charge accumulation occurs.
The new crystal modification III of torasemide prepared according to the process of the present invention can be used as a suitable torasemide form as a diuretic as well as an agent for preventing heart or heart tissue damages caused by metabolic or ionic abnormalities associated with ischemia, in the treatment of thrombosis, angina pectoris, asthma, hypertension, nephroedema, pulmonary edema, primary and secondary aldosteronism, Bartter""s syndrome, tumours, glaucoma, for decreasing intraocular pressure, acute or chronic bronchitis, in the treatment of cerebral edema caused by trauma, ischemia, concussion of the brain, metastases or epileptic attacks and in the treatment of nasal infections caused by allergens.
The present invention also relates to pharmaceutical forms such as tablets containing the new crystal modification III of torasemide as the active ingredient combined with one or more pharmaceutically acceptable additives such as sugar, starch, starch derivatives, cellulose, cellulose derivatives, mould release agents, and antiadhesive agents and possibly agents for flowability regulation. When using the new crystal modification III of torasemide for the preparation of pharmaceutical forms, also process steps taking place in water, e.g. granulation, can be used.
The starting materials for the process of present invention i.e the alkaline extract of the original reaction mixture for torasemide synthesis can be prepared according to DE 25 16 025, whereas the modifications I and II of torasemide can be prepared according to Acta Cryst. B34 (1978), 1304-1310.